Translating Time

Ever wonder approximately how old your brush-tailed opossum is equivalent to human years? Of course you have! Who hasn’t?

What about your spiny mouse? Your wallaby? Your gerbil or ferret?

Never fear. Dr. Christine Charvet, assistant professor in the Auburn University College of Veterinary Medicine, has got your back. A graduate of the University of California-Los Angeles and Cal-Irvine, she did her postdoctoral training in neuroimaging at Harvard Medical School and statistical genetics at Cornell University.

Afterward, she joined the faculty of Delaware State University and seemed destined for a career in human medicine before fulfilling a lifetime interest in animals by joining the veterinary faculty at Auburn.

“I always loved animals,” Charvet recalled. “I wanted to be a veterinarian before I became fascinated with neuroscience. That led to an early career in human medicine, but at Auburn I saw the opportunity to impact both animals and humans. It was the perfect opportunity.”

While at Cornell, she worked with the developers of a website called Translating Time (www.translatingtime.org)—a statistical model that equates the timing of brain developmental events across different mammalian species. The site uses behavioral, neurological and transcriptional markers to estimate equivalent stages of development between species as diverse as mice and humans. It currently features 19 mammals, but Charvet is dedicated to expanding both the number of species and range of ages included in the model.

In addition to humans, the site includes data for chimpanzees, macaques, several rodent species and six marsupials. The empirical data generating the model for each species comprises hundreds of prenatal developmental events, including measures of initial neurogenesis, axon extension and establishment, and refinement of brain connections. Later events, such as myelin formation, brain growth and early behavioral milestones, are also included. This now allows the model to predict equivalencies up to the third year of human postnatal life.

Originally, Charvet explained, the model largely focused on anatomical changes during species’ fetal development. “There are a number of abrupt transformational changes during that period,” she said, “that can be used to equate ages across species. But anatomy alone was not enough to extend the model across entire life spans.”

So Charvet and her team focus on utilizing a multi-omics approach, which integrates transcription, epigenetic and structural variation to expand the model’s data to determine equivalency across varying species’ lifetimes. That effort is particularly challenging because none of the other species—even chimpanzees, which she and the team added to the site’s species list—experience life spans as lengthy as humans.

“We quickly realized that one thing unique to humans compared to other apes is old age,” Charvet explained. “It is very rare for chimpanzees to live past 45 years, which roughly equates to the fifties in humans. That means the biological processes that occur in humans beyond their 60s are difficult to observe in great apes that do not live sufficiently long life spans for these biological processes to become manifest. That is problematic, because there are many health developments in human old age such as Alzheimer’s disease, and it is an open question as to whether there is a model that lives sufficiently long enough to recapitulate geriatric stages.

“Even though there are no clear counterparts to human old age, we are now looking at cats. We are focusing on capturing multi-omic metrics we can collect in their old age,” she added. “But their biological processes obviously differ more from humans.”

Even with the difficulties of finding equivalent comparisons for human old age, the data available from the Translating Time site has had many useful applications. One of those is for researchers studying mouse models of development. “One of the benefits of the site is that it helps researchers identify the best-suited stages to study different developmental processes and diseases,” Charvet noted. “So far, it has been cited in more than 680 individual research projects.”

The research also helped settle a long-standing scientific debate as to whether the human brain’s prefrontal cortex takes longer to develop than that in other primates, and whether this extended development is responsible for humans’ superior cognitive abilities. Charvet’s data seems to indicate that the answer is no. In fact, the circuitry of the human brain matures at a rate very similar to that of chimpanzees and macaques.

“It’s true that our development, and especially our life span, is extended compared with other primate species,” Charvet previously told The Academic Times. “But the question is, what is unusually extended after we control for the life span? We often talk about how human prefrontal cortex development should be extended relative to other primates. We’re just not finding it.”

There are many questions still to be answered and much more refinement of the model still ahead, but Charvet said she is in for the long haul. “It’s already a 25-year-old project, but it is exciting that we can employ the latest technologies and approaches to expand and grow this resource in ways that increase its utility for the biomedical community,” she concluded. “There are other species to be added, new types of data to include and new variations that will be more representative of diverse human populations. It’s an ongoing process.”